Cis-diamminedichloroplatinum (NSC-119875) in childhood malignancies: A southwest oncology group study

Children with malignancies resistant to conventional therapy were treated with cis-diamminedichloroplatinum (PDD), 1 5 to 20 mg/m², given daily by rapid intravenous infusion for 5 days at 3-wk intervals. Eleven of 24 children with acute lymphocytic leukemia (ALL) received two or more courses; among these no remissions occurred. Fifty-four children with solid tumors were treated: 25 neuroblastoma, 9 rhabdomyosarcoma, 4 Ewing sarcoma, 2 testicular embryonal carcinoma, 2 retinoblastoma, and 12 miscellaneous tumors. One complete remission, 3 partial remissions, and 2 improvements were observed in children with neuroblastoma. One girl with metastatic osteogenic sarcoma achieved a partial remission. One child with metastatic testicular embryonal carcinoma showed improvement. The side effects were vomiting controlled by antiemetics in 26 children and transient elevations of serum creatinine and BUN in 14 children. Nineteen of 39 children with solid tumors, who received more than one course of PDD, had moderately severe myelosuppression caused by PDD. In summary, PDD is a promising agent in neuroblastoma, osteogenic sarcoma, and testicular embryonal carcinoma, and an ineffective agent in ALL. The effect of PDD on other types of solid tumors should be evaluated in the future.     

Efficiency of Fine-Needle Aspiration Compared with Other Sampling Techniques for Laboratory Diagnosis of Buruli Ulcer Disease

In accordance with recent WHO recommendations, this study evaluates the sensitivities of PCR and microscopy for fine-needle aspiration (FNA) versus techniques involving swabs and punch biopsy specimens and suggests that FNA can replace punch biopsies for nonulcerative lesions and may serve as an alternative for ulcerative lesions in cases where scarred edges prevent the collection of swabs.Buruli ulcer disease (BUD), caused by Mycobacterium ulcerans, is an emerging disease predominantly affecting West and Central Africa. BUD initially presents as a painless nodule, papule, and plaque (nonulcerative lesions), evolving into a painless ulcer with characteristically undermined edges (ulcerative lesions). Scarring and contractures may cause severe functional disability (9, 11, 12). Among the currently available diagnostic laboratory methods (microscopy, culture, PCR, and histopathology), PCR provides the highest sensitivity and is therefore regarded as the method of choice for laboratory confirmation. The WHO encourages all countries where BUD is endemic to ensure PCR confirmation of at least 50% of all cases (1, 12, 13). With the introduction of antimycobacterial treatment, laboratory confirmation of suspect cases became crucial for clinical management of the disease (6, 12-15). Swabs, punch biopsy specimens, and surgically excised tissue are suitable diagnostic samples (3, 5-7). Recently, the WHO recommended fine-needle aspiration (FNA) as a minimally invasive method for nonulcerative lesions as well as for ulcerative lesions where scarring of edges prevents collection of swab samples (15).The present study retrospectively compares the sensitivities of PCR and microscopy for FNA samples, swabs, punch biopsy specimens, and surgically excised tissue.From February 2008 until December 2008, 173 clinically suspected BUD cases from Ghana (n = 112) and Togo (n = 61) were included in the study. FNA was performed with 21-gauge needles by transdermal aspiration. The needle was inserted into the center of the nonulcerative lesions or the subcutaneous tissue of the ulcer (the maximal distance from the margins was 1 to 2 cm) and was moved back and forth about three times in different directions under suction without withdrawal of the needle. Swabs, 3-mm punch biopsy specimens, and surgically excised tissue were taken according to standardized procedures, and all samples were stored in transport media as previously described and forwarded to the laboratories (5). In Ghana, 68 swabs, 112 FNA samples, 108 punch biopsy specimens, and 14 surgically excised tissue samples were subjected to microscopy and dry-reagent-based IS2404 PCR at the Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi (5, 10). The samples from Togo (43 swabs, 61 FNA samples, 45 punch biopsy specimens, and 7 surgically excised tissue samples) were analyzed at the Centre National de Référence et de Traitement d''Ulcère de Buruli, Tsévié (microscopy), and the Department of Infectious Diseases and Tropical Medicine, University of Munich, Germany (IS2404 standard PCR), in accordance with standardized procedures (5, 10).One hundred ten suspects (63.6%) with 37 (33.6%) nonulcerative lesions and 73 (66.4%) ulcerative lesions were confirmed by at least one positive test result. The categories of the lesions according to the WHO definitions were known for 107 of these cases (12) (category I, 49 cases [45.8%]; category II, 44 cases [41.1%]; and category III, 14 cases [13.1%]).Among the 37 nonulcerative cases, the sensitivities of PCR, defined as the number of positive test results divided by the number of laboratory-confirmed cases (5), were 88.9% (32/36) for FNA samples and 87.5% (28/32) for punch biopsy specimens, and the sensitivities of microscopy were 58.3% (21/36) for FNA samples and 55.6% (15/27) for punch biopsy specimens. For both tests, there was no significant difference in sensitivity between the two types of samples (the P value for PCR [P_PCR] was 0.86, and the P value for microscopy [P_microscopy] was 0.83) (Table ​(Table11).

TABLE 1.

Sensitivities of dry-reagent-based IS2404 PCR and microscopic examination^a

Human CD22 cannot fully substitute murine CD22 functions in vivo,as shown in a new knockin mouse model

CD22, an inhibitory co‐receptor of the B‐cell receptor, shows a B‐cell‐specific expression pattern and is expressed on most B‐cell lymphomas. The anti‐CD22 antibody Epratuzumab is in clinical trials for B‐cell non‐Hodgkin lymphoma and systemic lupus erythematosus, but shows a mostly unknown mode of action. We generated a new mouse model that expresses human CD22 instead of murine CD22 (Huki CD22 mice), in which human CD22 can be targeted. Expression of human CD22 on the B cells of Huki CD22 mice does not generally interfere with B‐cell development. However, Huki CD22 mice show a reduction of the population of mature recirculating B cells in the bone marrow and reduced transitional and marginal zone B cells in the spleen, phenotypes resembling that of CD22‐deficient mice. Similarly, enhanced BCR‐induced Ca²⁺ signalling is observed in Huki CD22 mice, which also mount normal immune responses toward different classes of antigens. Huki CD22 B cells show a normal anti‐hCD22 antibody‐mediated endocytosis. In conclusion, human CD22 cannot fully substitute for murine CD22 functions, possibly due to the changed intracellular tail of the protein or due to lower expression levels. Huki CD22 mice are a valuable new model for both antibody‐ and immunotoxin‐mediated targeting of human CD22.     

Collateral damage and compensatory changes after injection of a toxin targeting neurons with the neurokinin-1 receptor in the nucleus tractus solitarii of rat

Injection into the nucleus tractus solitarii (NTS) of toxins that target substance P (SP) receptors ablates neurons that express neurokinin-1 (NK1) receptors, attenuates baroreflexes, and results in increased lability of arterial pressure. We and others have shown that the toxin leads to loss of neurons containing SP receptors and loss of GABAergic neurons in the NTS; but given that neither type neuron is thought to be integral to baroreflex transmission in NTS, mechanisms responsible for the cardiovascular changes remained unclear. Because NK1 receptors colocalize with N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in NTS and because glutamate transmission may be integral to baroreflex transmission in the NTS we hypothesized that the toxic lesions may interrupt mechanisms for glutamate transmission. Interruption of those mechanisms could be responsible for the cardiovascular effects. We tested the hypothesis by performing fluorescent immunohistochemistry, confocal microscopy and image analysis after injecting stabilized SP-SAP (SSP-SAP) unilaterally into the NTS. We assessed changes in immunoreactivity (IR) of NMDA receptor subunit 1 (NMDAR1), AMPA receptor subunit 2 (GluR2), and 3 types of vesicular glutamate transporters (VGluT) as well as IR of gamma-aminobutyric acid receptors type b (GABAb), neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), and protein gene product 9.5 (PGP 9.5), a neuronal marker, in the NTS. When compared to that of the same section of the un-injected NTS, IR decreased significantly in the injected side for NMDAR1 (p<0.01), GluR2 (p<0.01), VGluT3 (p<0.01), GABAb (p<0.001), and PGP9.5 (p<0.001). In contrast, IR for VGluT1 (p<0.001), VGluT2 (p<0.001), nNOS (p<0.001), and TH (p<0.001) increased significantly. We conclude that pathologic effects following ablation of neurons with NK1 receptors in NTS may result from interruption of neurotransmission through other neurochemical systems associated with NK1 receptors-containing neurons.